Numerous growth factors have been identified for lung cancer including bombesin, epidermal growth factor, insulin-like growth factor and vasoactive intestinal peptide (VIP). VIP elevates the cAMP and stimulates lung cancer proliferation in an autocrine manner. The growth of lung cancer is inhibited by the VIP receptor antagonist VIPhybrid. Here human lung proteins were identified by Surface Enhanced Laser Desorption/Ionization (SELDI). Frozen sections of lung cancer were microdissected using laser capture techniques. Proteins were extracted using 6 N guanidine.HCl. The extracts were absorbed using a H4 chip and fractionated by SELDI. In tumor specimens from a squamous cell carcinoma and mesothelioma patient, numerous proteins were identified with mass/charge ratios of 3,196-3,477 daltons. In adjacent normal tissue, these proteins were present with 30-fold lower densities. Adjacent normal tissue was enriched in proteins with mass/charge ratios of 10,980-15,842 daltons relative to malignant tissue. Synthetic VIP, which has a Mr of 3,336 daltons, had a mass/charge ratio of 3,325 upon SELDI analysis. If the mesothelioma protein extract was immunoprecipitated with VIP antisera prior to SELDI, a peak around 3,300 disappeared from SELDI protein profile. It remains to be determined if VIP will be a useful biomarker for early detection of lung cancer.